The prototype atypical neuroleptic clozapine has enhanced therapeutic effects in otherwise treatment resistant patients with schizophrenia. We have carried out longitudinal clinical studies of the effects of clozapine on treatment resistant patients and have investigated mechanisms of clozapine action. Stemming from hypothesis based on the diverse receptor profile of clozapine, we have carried out clinical studies linking alterations in dopaminergic, serotonergic as well as noradrenergic function to the mechanism of clozapine action. Further, we have studied in vivo D2 occupancy using 123I-IBZM SPECT, and have observed that clozapine produces a wide range of D2 occupancy associated with favorable clinical response; there appears to be no critical degree of D2 occupancy required to maximize clozapine's effects. Further, we have carried out studies of atypical antipsychotics on regional glucose metabolism and have begun to examine these drugs effects on distributed neural networks. Finally, we have initiated studies into the pharmacogenetics of clozapine, specifically addressing the effects of allelic variation in neurotransmitter genes in relation to clozapine response.